Fragment screening for a protein-protein interaction inhibitor to WDR5
Fragment screening for a protein-protein interaction inhibitor to WDR5
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DOI：
10.1063/1.5122849
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发表时间：
2019-11-01
影响因子：
2.8
通讯作者：
Peat, Thomas. S.
中科院分区：
文献类型：
--
作者：
Dennis, Matthew L.;Morrow, Benjamin J.;Peat, Thomas. S.
WD 40重复蛋白WDR 5支架各种表观遗传作家，是哺乳动物SET/MLL组蛋白甲基转移酶复合物的关键组成部分。MLL 1催化功能的失调与混合谱系白血病相关，并且已经提出通过小分子拮抗WDR 5-MLL 1相互作用作为ML重排癌症的治疗策略。引起从染色质置换的WDR 5的“WIN”位点的小分子结合物已经另外暗示在癌症治疗中具有更广泛的用途。在这项研究中，使用表面等离子体共振（SPR）的片段筛选来鉴定结合在WIN位点中的高度配体有效的含咪唑化合物。随后的药物化学由一套高分辨率共晶结构与WDR 5引导，将最初的命中进展到低微摩尔粘合剂。这项研究的一个结果是取代精氨酸侧链的部分;含有一个这样的取代的三肽在高分辨率结构（1.5埃）中解析，结合模式类似于天然三肽。此外，SPR还表明这两种类似物的停留时间相似（k（d）=与0.06 s（-1）相似）。因此，这种新型支架代表了克服具有高碱性基团如胍的WDR 5配体的潜在渗透性问题的可能手段。本文报道的系列进一步了解了WDR 5 WIN位点，并作为开发更有效的WDR 5抑制剂的起点，这些抑制剂可用作癌症治疗剂。
The WD40-repeat protein WDR5 scaffolds various epigenetic writers and is a critical component of the mammalian SET/MLL histone methyltransferase complex. Dysregulation of the MLL1 catalytic function is associated with mixed-lineage leukemia, and antagonism of the WDR5-MLL1 interaction by small molecules has been proposed as a therapeutic strategy for MLL-rearranged cancers. Small molecule binders of the "WIN" site of WDR5 that cause displacement from chromatin have been additionally implicated to be of broader use in cancer treatment. In this study, a fragment screen with Surface Plasmon Resonance (SPR) was used to identify a highly ligand-efficient imidazole-containing compound that is bound in the WIN site. The subsequent medicinal chemistry campaign-guided by a suite of high-resolution cocrystal structures with WDR5-progressed the initial hit to a low micromolar binder. One outcome from this study is a moiety that substitutes well for the side chain of arginine; a tripeptide containing one such substitution was resolved in a high resolution structure (1.5 angstrom) with a binding mode analogous to the native tripeptide. SPR furthermore indicates a similar residence time (k(d) = similar to 0.06 s(-1)) for these two analogs. This novel scaffold therefore represents a possible means to overcome the potential permeability issues of WDR5 ligands that possess highly basic groups like guanidine. The series reported here furthers the understanding of the WDR5 WIN site and functions as a starting point for the development of more potent WDR5 inhibitors that may serve as cancer therapeutics.